All Nighter

Posted on 28 Dec 2013 @ 12:39am by Lieutenant Olsam Mott & Commander Allyndra illm Warraquim

2,300 words; about a 12 minute read

Mission: Episode 05 - Solstice
Location: Pasteur Institute, Paris, Earth
Timeline: MD 10 - 1610 hrs

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Olsam had used the train ride into Paris to further review the data on Inbriden. He'd been able to formulate a few rough ideas on tests to run to determine where the breakdown was occurring in digestion, as he was now increasingly convinced that's where the problem was beginning for the half-life of the drug.

Once he'd connected with Paris's transportation network, the trip to the institute had been a quick one. He'd decided to put the thoughts of research from his mind for the duration and just enjoy the Paris scenery, which always seemed to take on a somber elegance while under the threatening gaze of steel-gray snow clouds.

At the Pasteur Institute itself, Olsam queued up with the other researchers, clinicians, doctors and medical personnel to pass through security and gain admittance. Unsurprisingly for this time of the day there were more people exiting the building than entering; in fact, he probably could have delayed the work until the following day, but the idea was persistent and demanded some manner of inquiry to test its validity.

On the fourth floor he adjusted his lab coat and walked down a long hallway lined on either side with laboratory spaces behind glass walls. It always felt like a sort of gauntlet to Olsam, as if scientists would just start flinging test tubes and beakers at him while he made a mad dash for the lab space he was sharing with the rest of the Inbriden team.

Upon arriving at their lab, he entered his access code, scanned his retina and then slipped inside with a cheery greeting. "Hi, I'm back!"

Thomas looked up and sighed internally. "Crap," he thought to himself, "looks like another all nighter." Well it always seemed that way especially when you were a grad student. He was pretty well convinced that he and others like him were pretty much low paid slave labour.

"What's up Doc," Thomas said lightly figuring the Bolian had no idea what the reference was really to.

"Thomas, my boy!" Olsam said, slapping the young man on the back. Grad students were wonderful assistants, and the Bolian physician was glad to have him on the team. He also seemed to love working late hours, which they were definitely in for. "What's up? Um. Is this a riddle? I suppose it would depend on your perspective, really... Let's see, what's up from where I am? Or...you?" He narrowed his eyes in suspicion. "Is this a trick question?"

Thomas just rolled his eyes. He was just getting in deeper and if he did not nip this it would turn into an hour and half of just trying to explain or dance around everything. "Just asking what brings you into the lab this TIME of day. Thought you had gone home." Thomas lightly emphasized the word but he doubted the doctor would care. "Something on your mind?"

Olsam wasn't sure what his method of conveyance had to do with anything, but young people were an inquisitive sort. "Well, first I was brought here by the train from Crecy-la-Chapelle to Paris, and then I took the Metro before walking the rest of the way here." He paused and shuffled through some files on a computer terminal before activating a spinning, three-dimensional view of Inbriden on the holoprojector. "Something is on my mind. Aside from the ordinary cerebrospinal fluid, that is. I think I have a hypothesis about the half-life...or the beginning of a hypothesis, anyway."

Thomas wanted to groan as the Bolian took everything literally but finally he seemed to get to the gist of what brought him here and as Olsam brought up the holo-projection of the molecule Thomas forgot about crashing on his sofa with a beer and peered at the molecule. His attention was now focused, the scientific curiosity overcoming everything else.

"So, ordinarily, we develop drugs for delivery through hypospray, yes?"

"Most of the time, yes. There are exceptions." Thomas could think of half a dozen that were by other means.

"And yet, this one isn't suitable for that." He paused and gestured toward different portions of the drug that presented unstable behavior when introduced via hypospray. "So we're giving it in an ingestible tablet form. See? Ingestible! It's being introduced into the body through a system completely separate from the circulatory system. Where the circulatory system is usually at the forefront of drug delivery, now it's taking a backseat to the digestive system in the initial stages of introduction. I believe there's something about digestion that's affecting the bioavailability, so that's where we'll begin."

Olsam glanced up at the chronometer on the wall.

"Hm. Well. Did you have anything to do this evening? I mean, you should be out of here by 0100 or something along those lines. That leaves plenty of time until 0800, right?"

Thomas thought about what Olsam was saying and new thoughts came into his own head. When the Bolian asked him about leaving he only shook his head in the negative. "No, no place in particular. I got a replicator over there that makes a good strong cup of joe, coffee. I think I live on caffine." Thomas replied with a lot more enthusiasm in his voice.

"Well Imbredin has to go long term to be effective and no one wants to be having daily shots, hence why oral with a slower absorption, but......" Thomas got a clue to what the Bolian might be talking about. "Your thinking that the first pass metabolism is responsible for poor performance." He pointed to a section, "right here we have seen this metabolite, an addition of a hydroxyl group that makes it excretable by the kidneys."

"Good catch, Thomas! And that metabolite is only the first of the problems. Take a look at the whole structure - you see it's hydrophilic enough to just be shuttled right off to the liver - and then when you get down closer you'll see any number of issues leading to the first-pass problem, as you pointed out," Olsam said excitably.

He tapped a few more commands into the console and brought up a scrolling list of species. "These are the species with the poorest performance. Out of those species...," a few more commands and some species jumped out of the list into a separate column, "...we end up with these as the lowest performers. See anything in common? It didn't hit me until I saw Bolians there. Every species here is notable for its high rate of digestive metabolism."

Olsam closed down the list and enhanced the chemical composition of the drug again.

"I think the sensible hypothesis is to investigate the problems with first-pass. It's just a hunch after all. We can work on solutions once we've more solidly identified the problem."

"Cool!" Thomas felt the weariness of the day lift. "Let me pull some blood samples and take a look at the metabolites."

"Wonderful!"

--Several hours later--

"Hey doc! I just got the mass spec results. Almost every species and even more strongly in the species you mentioned have this hydroxylation at the sixth carbon position. Bolians about a ninety eight percent conversion rate on first pass. So the pharmacodynamics is definitely being tossed off. I took a look at some modifications but a tri-fluoro group just kicks the potency in the ass. So looks like back to square one."

"The tri-fluoro group was a good idea, Thomas, but the drug's stability is just so touchy," Olsam mumbled while looking at the results on the PADD he was handed. He glanced up at the rotating drug being displayed by the lab's holoprojector and then zoomed in on the sixth carbon position, where the hydroxylation problems were cropping up.

He joined his research assistant in staring at the holographic projection for several long moments. The string of molecules was spinning slowly in the air and even within each atom one could barely make out simulated electrons spinning wildly around clustered protons and neutrons - layers within layers. Three fluorine atoms were displayed among the other molecules, the result of Thomas's last attempt to block enzyme interaction with the drug. Olsam reached up, interacting with the hologram to detach the three atoms of fluorine.

"Maybe not back to 'square one,'" Olsam said, though he had no idea what the expression meant. Sometime he found just mimicking what a person said let him get away with being ignorant to colloquial phrases. He turned back to the computer console, used his personal access codes to connect with Starfleet Medical's database, and began running queries. "What if instead of trying to block metabolism, we bypass it altogether? I think I remember reading a paper about someone using a prodrug..."

"Prodrug?" Thomas inquired wrinkling his brow. "Administer as an inactive form to let metabolism make it active. I suppose it is a thought. Might help absorption but we still got first pass problems."

Olsam continued scanning through the studies and papers that his query generated within the database until finally he found the one he was looking for. "Here it is! They were seeing significant declines in bioavailability after oral administration of their drug compared to intravenous administration, so they created a prodrug that avoided presystemic metabolism."

Thomas peered over the Bolian's shoulder scanning the abstract to the article.
He muttered to himself though it would be right in Olsam's ear. "A modification to an orally active drug to increase lipophilicity in order to avoid first pass metabolism by increasing lymphatic absorption."

"Your thinking maybe adding a lipophilic tail so the drug gets dumped into the lympatics rather than blood initially. Interesting..." Thomas turned back to the molecule that was gently spinning slowly in all its holographic display.

"Here, we could try putting a lipophilic group here. That changes the Log D of Imbriden to lipophilic and should cleave right off once its in the cells." Thomas was still half muttering but as the whole idea struck him he brightened. "Let's get a model set up and test it. I'll see about getting a proper group and well, doc you want to work on an excipient for delivery?"

Olsam nodded. "Let's just hope it works and the whole thing doesn't keep up its very annoying pattern of falling apart every time we apply a work-around."

=-=-=-=-=

Dr. Olsam pulled up common excipients in the Pasteur Institute's database and began cross-checking for any undesirable responses with Inbriden. The computer began running through all manner of binders, fillers, lubricants, sorbents and other substances to generate a short-list for the doctor, who subsequently reviewed it and shortened it further based on his own knowledge of pharmacokinetics.

"Um, Thomas?" he said, pulling the data onto a PADD and walking over to the graduate student's station. "Would you mind taking a look at these proposed excipients and double-check them for me? I think I've found a good balance, but I'd like your opinion."

One of the more positive aspects of Olsam's very Bolian personality was the desire to work in a group setting - the brilliance of such teamwork, in his mind, was that team members could verify and assist one another in their work. Never one for pride or hubris, he would readily admit pharmacokinetics was hardly one of his most practiced or well-honed skills and while Thomas might be "just" a graduate student, it was nevertheless important to Olsam to call in his expertise since Thomas was likely to be living and breathing this stuff day in and day out in the course of his studies and lab work.

Thomas perused the list. "They all look very good to me. This one here should be easy enough to capsulate, let's go with this one. Let me get a test set up and see if we can avoid the first pass metabolism."

That was one nice thing over two centuries back is that one did not have to wait on days and weeks to test things out. The modeling concepts had come so far that one could predict with a high degree of accuracy just how well a real world test would work out.

Still it took a few hours to get all the parameters figured in but the test was ready. The modeling went through and sure enough the molecule got bundled up and put into a chylomicron. The half-life went way up and from the pharmacodynamics indicated that therapeutic levels were really good.

That was with a human physiology but resetting for some of the more different species settings still seemed to give a good test. In fact, one of the last one's was with Bolian specifications. They had a very corrosive system but even there the results were good.

Thomas yawned and looking up from the last results he saw that the sun was coming up. "Well doc, looks good on the modeling even your own kind the levels seem to add up. I think D'Tries is going to be very happy with this and probably want to start some new clinical trials again." Thomas yawned again.
"Come on doc, let's get some coffee or I am going to drop dead asleep in the data."

Olsam tried to hide his look of alarm - dead asleep did not sound like a good condition. "Yes, let's do that immediately."

The look on the Doc's face was priceless and Thomas would have appreciated it a lot more if he was not ready to fall over. "Yeah, sounds real good come on, a small victory celebration even if it is machine food and coffee."

[ OFF ]

Lieutenant JG Olsam Mott, M.D.
Assistant Chief Medical Officer
USS Galileo

&

Thomas (NPC'd by Allyndra illm Warraquim)
Grad student
Pasteur Institute

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